Nucynta

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Nucynta

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Abuse Potential

NUCYNTA® contains tapentadol, an opioid
agonist and a Schedule II controlled substance. Tapentadol can be abused in a
manner similar to other opioid agonists legal or illicit. Opioid agonists are
sought by drug abusers and people with addiction disorders and are subject to
criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® in situations where there is concern about increased risks of misuse,
abuse, or diversion. Concerns about abuse, addiction, and diversion should not,
however, prevent the proper management of pain.

Assess each patient's risk for opioid abuse or addiction
prior to prescribing NUCYNTA®. The risk for opioid abuse is
increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major
depression). Patients at increased risk may still be appropriately treated with
opioids; however these patients will require intensive monitoring for signs of
misuse, abuse, or addiction. Routinely monitor all patients receiving opioids
for signs of misuse, abuse, and addiction because these drugs carry a risk for
addiction even under appropriate medical use.

Misuse or abuse of NUCYNTA® by injecting the
oral solution will pose a significant risk that could result in overdose and
death [seeOVERDOSAGE].

Contact local state professional licensing board or state
controlled substances authority for information on how to prevent and detect
abuse or diversion of this product [seeDrug Abuse and Dependence].

Life Threatening Respiratory Depression

Respiratory depression is the chief hazard of opioid
agonists, including NUCYNTA® . Respiratory depression, if not
immediately recognized and treated, may lead to respiratory arrest and death.
Respiratory depression from opioids is manifested by a reduced urge to breathe
and a decreased rate of respiration, often associated with a “sighing” pattern
of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide
(CO2) retention from opioid-induced respiratory depression can exacerbate the
sedating effects of opioids. Management of respiratory depression may include
close observation, supportive measures, and use of opioid antagonists,
depending on the patient's clinical status [seeOVERDOSAGE].

Instruct patients against use by individuals other than
the patient for whom NUCYNTA® was prescribed and to keep NUCYNTA® out of the reach of children, as such inappropriate use may result in
fatal respiratory depression.

Patients with conditions accompanied by hypoxia,
hypercarbia or decreased respiratory reserve such as: asthma, chronic
obstructive pulmonary disease or cor pulmonale, central nervous system (CNS)
depression, or coma may be at increased risk for increased airway resistance
and decreased respiratory drive to the point of apnea even with usual
therapeutic doses of NUCYNTA®. Consider the use of alternative
non-mu-opioid agonist analgesics and use NUCYNTA® only under careful
medical supervision at the lowest effective dose in such patients. If
respiratory depression occurs, treat the patient for mu-opioid agonist-induced
respiratory depression [seeOVERDOSAGE]. To reduce the risk of
respiratory depression, proper dosing of NUCYNTA® is essential [seeDOSAGE AND ADMINISTRATION].

Accidental Exposure

Accidental ingestion of NUCYNTA®, especially
in children, can result in a fatal overdose of tapentadol.

Interactions With Alcohol, Other Opioids, And Drugs Of Abuse

Due to its mu-opioid agonist activity, NUCYNTA® may
be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression,
respiratory depression, hypotension, and profound sedation, coma or death [seeDRUG INTERACTIONS]. Instruct patients not to consume alcoholic beverages or
use prescription or non-prescription products containing alcohol, other
opioids, or drugs of abuse while on NUCYNTA® therapy [seeDRUG
INTERACTIONS].

Elderly, Cachectic, And Debilitated Patients

Respiratory depression is more likely to occur in
elderly, cachectic, or debilitated patients as they may have altered
pharmacokinetics or altered clearance compared to younger, healthier patients.
Therefore, closely monitor such patients, particularly when NUCYNTA® is
given concomitantly with other drugs that depress respiration [see Life Threatening Respiratory Depression].

Use In Patients With Chronic Pulmonary Disease

Monitor for respiratory depression those patients with
significant chronic obstructive pulmonary disease or cor pulmonale, and
patients having a substantially decreased respiratory reserve, hypoxia,
hypercarbia, or pre-existing respiratory depression, as in these patients, even
usual therapeutic doses of NUCYNTA® may decrease respiratory drive
to the point of apnea [see Life Threatening Respiratory Depression]. Consider the use
of alternative non-opioid analgesics in these patients if possible.

Interactions With CNS Depressants And Illicit Drugs

Hypotension, and profound sedation, coma or respiratory
depression may result if NUCYNTA® is used concomitantly with other
CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle
relaxants, other opioids and illicit drugs). When considering the use of
NUCYNTA® in a patient taking a CNS depressant, assess the duration
of use of the CNS depressant and the patient's response, including the degree
of tolerance that has developed to CNS depression. Additionally, consider the
patient's use, if any, of alcohol and/or illicit drugs that can cause CNS
depression. If NUCYNTA® therapy is to be initiated in a patient
taking a CNS depressant, start with a lower NUCYNTA® dose than usual
and monitor patients for signs of sedation and respiratory depression and
consider using a lower dose of the concomitant CNS depressant [see DRUG
INTERACTIONS].

Hypotensive Effect

NUCYNTA® may cause severe hypotension. There
is an increased risk in patients whose ability to maintain blood pressure has
already been compromised by a reduced blood volume or concurrent administration
of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [seeDRUG INTERACTIONS]. Monitor these patients for signs of hypotension after
the dose of NUCYNTA®. In patients with circulatoryshock, NUCYNTA® may cause vasodilation that can further reduce cardiac output and blood
pressure. Avoid the use of NUCYNTA® in patients with circulatory
shock.

Use In Patients With Head Injury Or Increased
Intracranial Pressure

Monitor patients taking NUCYNTA® who may be
susceptible to the intracranial effects of CO2 retention (e.g., those with
evidence of increased intracranial pressure or brain tumors) for signs of
sedation and respiratory depression. NUCYNTA® may reduce respiratory
drive, and the resultant CO2 retention can further increase intracranial
pressure. Opioids may also obscure the clinical course in a patient with a head
injury.

Avoid the use of NUCYNTA® in patients with
impaired consciousness or coma.

Seizures

NUCYNTA® has not been evaluated in patients
with a predisposition to a seizure disorder, and such patients were excluded
from clinical studies. The active ingredient tapentadol in NUCYNTA® may
aggravate convulsions in patients with convulsive disorders, and may induce or
aggravate seizures in some clinical settings. Monitor patients with a history
of seizure disorders for worsened seizure control during NUCYNTA® therapy.

Use In Patients With Gastrointestinal Conditions

NUCYNTA® is contraindicated in patients with
GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® may
cause spasm of the sphincter of Oddi. Monitor patients with biliary tract
disease, including acute pancreatitis, for worsening symptoms.

Driving And Operating Heavy Machinery

NUCYNTA® may impair the mental or physical
abilities needed to perform potentially hazardous activities such as driving a
car or operating machinery. Warn patients not to drive or operate dangerous
machinery unless they are tolerant to the effects of NUCYNTA® and
know how they will react to the medication.

Hepatic Impairment

A study with NUCYNTA® in subjects with hepatic
impairment showed higher serum concentrations of tapentadol than in those with
normal hepatic function. Avoid use of NUCYNTA® in patients with
severe hepatic impairment. Reduce the dose of NUCYNTA® in patients
with moderate hepatic impairment [seeDOSAGE AND ADMINISTRATION and CLINICAL
PHARMACOLOGY]. Closely monitor patients with moderate hepatic impairment
for respiratory and central nervous system depression when receiving NUCYNTA® .

Renal Impairment

Use of NUCYNTA® in patients with severe renal
impairment is not recommended due to accumulation of a metabolite formed by
glucuronidation of tapentadol. The clinical relevance of the elevated
metabolite is not known [seeCLINICAL PHARMACOLOGY].

Patient Counseling Information

Inform patients of the availability of a Medication Guide
and Instructions for Use, and instruct them to read the Medication Guide and
Instructions for Use prior to taking NUCYNTA® oral solution.

Instruct patients to take NUCYNTA® oral
solution only as prescribed.

Abuse Potential

Inform patients that NUCYNTA® contains
tapentadol, a Schedule II controlled substance that is subject to abuse. Instruct
patients not to share NUCYNTA® with others and to take steps to
protect NUCYNTA® from theft or misuse.

Life-threatening Respiratory Depression

Discuss the risk of respiratory depression with patients,
explaining that the risk is greatest when starting NUCYNTA® or when
the dose is increased. Advise patients how to recognize respiratory depression
and to seek medical attention if they are experiencing breathing difficulties.

Accidental Exposure

Instruct patients to take steps to store NUCYNTA® securely.
Accidental exposure, especially in children, may results in serious harm or
death. Advise patients to dispose of unused NUCYNTA® by flushing the
oral solution down the toilet.

Important Administration Instructions

Instruct patients how to properly take NUCYNTA® oral
solution, including the following:

Advise patients to always use the enclosed calibrated
oral syringe when administering NUCYNTA® oral solution to ensure the
dose is measured and administered accurately.

Not discontinuing NUCYNTA® without first
discussing the need for a tapering regimen with the prescriber.

Risks from Concomitant Use of Alcohol and other CNS
Depressants

Inform patients that the concomitant use of alcohol with
NUCYNTA® can increase the risk of life-threatening respiratory
depression. Instruct patients not to consume alcoholic beverages, as well as
prescription and over-the-counter drug products that contain alcohol, during
treatment with NUCYNTA® .

Inform patients that potentially serious additive effects
may occur if NUCYNTA® is used with other CNS depressants, and not to
use such drugs unless supervised by a health care provider.

Concurrent use of MAOI

Inform patients not to take NUCYNTA® while
using any drugs that inhibit monoamine oxidase. Patients should not start any
new medications while taking NUCYNTA® .

Seizures

Inform patients that NUCYNTA® could cause
seizures if they are at risk for seizures or have epilepsy. Patients should be
advised to stop taking NUCYNTA® if they have a seizure while taking
NUCYNTA® and call their healthcare provider right away.

Serotonin Syndrome

Inform patients that NUCYNTA® could cause a rare
but potentially life-threatening condition resulting from concomitant
administration of serotonergic drugs (including Serotonin Reuptake Inhibitors,
Serotonin and Norepinephrine Reuptake Inhibitors and tricyclic antidepressants.
Warn patients of the symptoms of serotonin syndrome and to seek medical
attention right away if symptoms develop.

Instruct patients to inform their physicians if they are
taking, or plan to take additional medications including CNS Depressants, MAO
inhibitors, mixed agonists/antagonist opioid analgesics, anticholinergics,
SSRIs, SNRIs, or tricyclic antidepressants.

Hypotension

Inform patients that NUCYNTA® may cause
orthostatic hypotension and syncope. Instruct patients how to recognize
symptoms of low blood pressure and how to reduce the risk of serious
consequences should hypotension occur (e.g., sit or lie down, carefully rise
from a sitting or lying position).

Driving or Operating Heavy Machinery

Inform patients that NUCYNTA® may impair the
ability to perform potentially hazardous activities such as driving a car or
operating heavy machinery. Advise patients not to perform such tasks until they
know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention.

Anaphylaxis

Inform patients that anaphylaxis has been reported with
ingredients contained in NUCYNTA® . Advise patients how to recognize
such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that NUCYNTA® can cause
fetal harm and to inform the prescriber if they are pregnant or plan to become
pregnant.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Tapentadol was administered to rats (diet) and mice (oral
gavage) for two years.

In mice, tapentadol HCl was administered by oral gavage
at dosages of 50, 100 and 200 mg/kg/day for 2 years (up to 0.2 times the plasma
exposure at the maximum recommended human dose [MRHD] on an area under the
time-curve [AUC] basis). No increase in tumor incidence was observed at any
dose level.

In rats, tapentadol HCl was administered in diet at
dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.2 times in the
male rats and 0.6 times in the female rats the MRHD on an AUC basis). No
increase in tumor incidence was observed at any dose level.

Mutagenesis

Tapentadol did not induce gene mutations in bacteria, but
was clastogenic with metabolic activation in a chromosomal aberration test in
V79 cells. The test was repeated and was negative in the presence and absence
of metabolic activation. The one positive result for tapentadol was not
confirmed in vivo in rats, using the two endpoints of chromosomal aberration
and unscheduled DNA synthesis, when tested up to the maximum tolerated dose.

Impairment of Fertility

Tapentadol HCl was administered intravenously to male or
female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up
to approximately 0.4 times the exposure at the MRHD on an AUC basis, based on
extrapolation from toxicokinetic analyses in a separate 4-week intravenous
study in rats). Tapentadol did not alter fertility at any dose level. Maternal
toxicity and adverse effects on embryonic development, including decreased
number of implantations, decreased numbers of live conceptuses, and increased
pre- and post-implantation losses occurred at dosages ≥ 6 mg/kg/day.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and
well-controlled studies of NUCYNTA® in pregnant women. NUCYNTA® should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.

Tapentadol HCl was evaluated for teratogenic effects in
pregnant rats and rabbits following intravenous and subcutaneous exposure
during the period of embryofetal organogenesis. When tapentadol was
administered twice daily by the subcutaneous route in rats at dose levels of
10, 20, or 40 mg/kg/day [producing up to 1 times the plasma exposure at the
maximum recommended human dose (MRHD) of 700 mg/day based on an area under the
time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of
embryofetal toxicity included transient delays in skeletal maturation (i.e.
reduced ossification) at the 40 mg/kg/day dose which was associated with
significant maternal toxicity. Administration of tapentadol HCl in rabbits at
doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.2, 0.6,
and 1.85 times the plasma exposure at the MRHD based on an AUC comparison]
revealed embryofetal toxicity at doses ≥ 10 mg/kg/day. Findings included
reduced fetal viability, skeletal delays and other variations. In addition,
there were multiple malformations including gastroschisis/thoracogastroschisis,
amelia/phocomelia, and cleft palate at doses ≥ 10 mg/kg/day and above,
and ablepharia, encephalopathy, and spina bifida at the high dose of 24
mg/kg/day. Embryofetal toxicity, including malformations, may be secondary to
the significant maternal toxicity observed in the study.

In a study of pre- and postnatal development in rats,
oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to
pregnant and lactating rats during the late gestation and early postnatal
period [resulting in up to 1.7 times the plasma exposure at the MRHD on an AUC
basis] did not influence physical or reflex development, the outcome of
neurobehavioral tests or reproductive parameters. Treatment-related
developmental delay was observed, including incomplete ossification, and
significant reductions in pup body weights and body weight gains at doses
associated with maternal toxicity (150 mg/kg/day and above). At maternal
tapentadol doses ≥ 150 mg/kg/day, a dose-related increase in pup
mortality was observed through postnatal Day 4.

Labor And Delivery

NUCYNTA® is not for use in women during and
immediately prior to labor. Occasionally, opioid analgesics may prolong labor
by temporarily reducing the strength, duration, and frequency of uterine
contractions. However, these effects are not consistent and may be offset by an
increased rate of cervicaldilatation which tends to shorten labor.

Opioids cross the placenta and may produce respiratory
depression and psychophysiologic effects in neonates. Closely observe neonates
whose mothers received opioid analgesics during labor for signs of respiratory
depression. An opioid antagonist, such as naloxone, should be available for
reversal of opioid-induced respiratory depression in the neonate in such
situations.

Nursing Mothers

There is insufficient/limited information on the
excretion of tapentadol in human or animal breast milk. Physicochemical and
available pharmacodynamic/toxicological data on tapentadol point to excretion
in breast milk and risk to the breastfeeding child cannot be excluded.

Because of the potential for adverse reactions in nursing
infants from NUCYNTA®, a decision should be made whether to
discontinue nursing or discontinue the drug, taking into account the importance
of the drug to the mother.

Withdrawal symptoms can occur in breast-feeding infants
when maternal administration of NUCYNTA® is stopped.

Pediatric Use

The safety and effectiveness of NUCYNTA® in
pediatric patients less than 18 years of age have not been established.

Geriatric Use

Of the total number of patients in Phase 2/3
double-blind, multiple-dose clinical studies of NUCYNTA®, 19% were
65 and over, while 5% were 75 and over. No overall differences in effectiveness
were observed between these patients and younger patients. The rate of
constipation was higher in subjects greater than or equal to 65 years than
those less than 65 years (12% vs. 7%).

In general, recommended dosing for elderly patients with
normal renal and hepatic function is the same as for younger adult patients
with normal renal and hepatic function. Because elderly patients are more
likely to have decreased renal and hepatic function, consideration should be
given to starting elderly patients with the lower range of recommended doses [see
CLINICAL PHARMACOLOGY].

Neonatal Withdrawal Syndrome

Chronic maternal use of NUCYNTA® during
pregnancy can affect the neonate with subsequent withdrawal signs. Neonatal
withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep
pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain
weight. The onset, duration and severity of neonatal withdrawal syndrome vary
based on the drug used, duration of use, the dose of last maternal use, and
rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome
may be life-threatening and should be treated according to protocols developed
by neonatology experts.

Renal Impairment

The safety and effectiveness of NUCYNTA® has
not been established in patients with severe renal impairment (CLCR < 30
mL/min). Use of NUCYNTA® in patients with severe renal impairment is
not recommended due to accumulation of a metabolite formed by glucuronidation
of tapentadol. The clinical relevance of the elevated metabolite is not known [see
CLINICAL PHARMACOLOGY].

Hepatic Impairment

Administration of tapentadol resulted in higher exposures
and serum levels of tapentadol in subjects with impaired hepatic function
compared to subjects with normal hepatic function [seeCLINICAL PHARMACOLOGY].
The dose of NUCYNTA® should be reduced in patients with moderate
hepatic impairment (Child-Pugh Score 7 to 9) [seeDOSAGE AND ADMINISTRATION].

Use of NUCYNTA® is not recommended in patients
with severe hepatic impairment (Child-Pugh Score 10 to 15) [see WARNINGS AND
PRECAUTIONS].

Last reviewed on RxList: 12/4/2014
This monograph has been modified to include the generic and brand name in many instances.